(+)-pilocarpine, (3S-cis)-3-ethyldihydro-4-[(1-methyl-1H -imidazol-5-yl)methyl]-2(3H)-furanone, is a drug which is used for the treatment of glaucoma, which lowers the ocular pressure by increasing the flow of chamber fluid from the eye. The intraocular pressure reducing effect of pilocarpine is based on the ciliary muscle contracting effect of the drug widening the angle of the anterior chamber which is important from the viewpoint of the outflow of the chamber fluid and the outflow of the fluid is facilitated.
The reduction of the intraocular pressure is, however, not the only effect of pilocarpine in the eye. When the drug concentration is sufficiently high, the contracting effect of pilocarpine on the ciliary muscle is increased, resulting in the adaptation of the ocular lens for seeing at close distance. It is then difficult for the patient to accommodate the eye for seeing at a greater distance, which is inconvenient for the patient. Pilocarpine also causes the iris of the eye to contract, the pupil of the eye decreasing considerably. Besides these effects on the eye which are unnecessary from a medical point of view and unpleasant for the patient, pilocarpine may cause side effects outside the eye. Such effects are i.a. increased salivation and bradycardia. Conventionally glaucoma patients administer pilocarpine locally as eyedrops. Administered in such a manner, however, only about 1% of the pilocarpine dose is absorbed by the eye and about 70% in the blood stream. The low absorption rate of pilocarpine in the eye is due to three major factors:
1) the drop is quickly flushed away from the surface of the eye PA0 2) the rapid absorbance of pilocarpine into the blood stream through the conjunctiva of the inner surface of the eyelid PA0 3) the poor corneal penetration capability of pilocarpine. PA0 Melting point determination: Reichert Thermovar apparatus PA0 Determination of refraction index: Atago Illuminator apparatus PA0 pKa-value determination: titrating the derivative in a water-ethanol mixture (50%-50%) PA0 Mass spectrometer: VG 70-250SE PA0 Thermospray-mass spectrometer: VG thermospray/plasmaspray VG Trio-2 quadropole Beckmann 112 pump PA0 NMR-spectrometer: Bruker AC 250/Aspect 3000
Pilocarpine is absorbed into the eye through the cornea. In the cornea it is first absorbed in the dense epithelium layer on the eye surface containing cell membrane lipids (fats) in abundance. However, pilocarpine is not very fat soluble wherefore it penetrates relatively little into the corneal epithelium. The corneal epithelium functions simultaneously as a film restricting the absorption of pilocarpine, and as a storage, which delivers pilocarpine through the aqueous stroma and endothelium of the cornea into the fluid of the anterior chamber. From the chamber fluid pilocarpine has easy access to its action site, the ciliary muscle. The duration of the effect of pilocarpine in the eye is substantially reduced by its partial conversion to inactive pilocarpic acid and the rapid departure of pilocarpine from the eye through the chamber fluid circulation and the blood circulation of the iris.
The low absorption into the inner parts of the eye and the short duration of action of pilocarpine administered into the eye cause difficulties in drug treatment. In order to improve the action of the drug and increase its duration of action, pilocarpine must be used in relatively big doses. From this follows that high pilocarpine levels are obtained in the chamber fluid, in the iris and the ciliary muscle which lead to a strong contraction of the pupil and adaptation of the eye to seeing at close distance. Increasing the dose of pilocarpine is, in addition, a relatively ineffective way of prolonging the action of the drug, the drug being of the type that is rapidly excreted from the eye, and thus pilocarpine eyedrops are administered 3 to 8 times daily depending on the patient. Administration of eyedrops so frequently is inconvenient from the point of view of the patient, especially when the administration of the drops is always followed by side effects in the eye. The use of big doses also increase the amount of pilocarpine absorbed in the blood circulation and thus also the risk for other side effects.
Efforts have been aimed at solving the afore said disadvantages relating to the poor absorption of pilocarpine by using pilocarpine prodrug derivatives which absorb better into the corneal epithelium. Such derivatives have to be more fat soluble than pilocarpine in order to improve absorption. In addition, they have to degrade as completely as possible in the corneal epithelium to liberate the pharmaceutically effective pilocarpine and the ineffective pro-moiety. The degree of degradation in the cornea is dependant on the residence time of the derivative in the corneal epithelium and its degradation rate therein. The residence time of the derivative in the epithelium is increased with increased lipophilicity and decreased diffusion coefficient.
Up to now two kinds of prodrug derivatives of pilocarpine have been developed. Bodor discloses in the U.S. Pat. No. 4,061,722 pilocarpine prodrugs based on quaternary ammonium compounds. Bundgaard et al. have disclosed in EP-patent application 0 106 541 pilocarpic acid diesters, by means of which improved ocular absorption has been reached. The said pilocarpic diesters are, however, associated with certain disadvantages, such as poor aqueous solubility and eye irritation. Also, a great number of undesirable side products are released from the diesters as compared to the active agent itself, pilocarpine.
The present invention relates to novel bispilocarpic acid esters, i.e. bispilocarpates, by means of which the aforementioned disadvantages may largely be eliminated or at least minimized. Thus the prodrug derivatives according to the invention degrade at least as rapidly to pilocarpine and the pro-moiety when compared to the prodrugs of Bundgaard et al. of corresponding lipophilicity, and they also promote at least to the same degree the penetration of pilocarpine through the cornea. In addition, the bispilocarpate derivatives carry into the cornea one pro-moiety for every two pilocarpine molecules, whereas the derivatives of Bundgaard et. al carry one pro-moiety for every pilocarpine molecule. The diffusion coefficients of the bispilocarpate derivatives in the corneal epithelium is smaller than those of the Bundgaard compounds, wherefore still undegraded bispilocarpate derivatives remain in the corneal epithelium longer. Thus there will be more time left for the prodrug to break down completely. In addition, the novel compounds of the invention have a better solubility, and are thus better suited for the preparation of drug formulations.
Thus the invention allows for extended slow drug release from the cornea into the inner parts of the eye, by means of which it is possible to effectively prolong the duration of action of pilocarpine and also reduce the peaks of high pilocarpine concentration in the eye, which is of importance from the view of reducing the afore mentioned side effects.